AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling.
AIBP Limits Angiogenesis Through γ-Secretase-Mediated Upregulation of Notch Signaling.
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DOI：
10.1161/circresaha.116.309754
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发表时间：
2017-05-26
影响因子：
20.1
通讯作者：
Fang L
中科院分区：
文献类型：
--
作者：
Mao R;Meng S;Gu Q;Araujo-Gutierrez R;Kumar S;Yan Q;Almazan F;Youker KA;Fu Y;Pownall HJ;Cooke JP;Miller YI;Fang L
血管生成改善急性血管阻塞后缺血组织的灌注。病理生理条件下的血管生成重新激活了与发育性血管生成有关的信号通路。我们之前的研究表明，apoA-I结合蛋白（AIBP）调节内皮细胞（ECs）中的胆固醇外排控制斑马鱼胚胎血管生成。本研究旨在确定AIBP缺失是否会影响小鼠在发育和病理条件下的血管生成，并探讨其潜在的分子机制。在本文中，我们报道了AIBP敲除（Apoa1bp - / -）小鼠的产生，其特征是出生后视网膜血管生成加速。在机制上，AIBP触发γ-分泌酶从脂质筏向非脂质筏的重新定位，并在那里切割Notch。与此一致的是，AIBP治疗增强了dll4刺激的人视网膜内皮细胞中的Notch激活。通过将Apoa1bp - / -小鼠与apoa - 1转基因小鼠杂交，可提高Apoa1bp - / -小鼠的HDL水平，从而挽救Notch激活并纠正视网膜血管生成失调。值得注意的是，Apoa1bp - / -小鼠的视网膜血管表现出正常的周细胞覆盖和血管完整性。同样，在模拟缺血/炎症性新生血管的皮下基质塞实验中，Apoa1bp - / -小鼠的血管生成显著上调，并与Notch激活的深度抑制和下游靶点的表达减少有关。此外，在小鼠后肢缺血模型中，AIBP的缺失增加了血管密度，促进了血管灌注功能的恢复。此外，AIBP在人类缺血性心肌病患者中的表达显著升高。我们的数据揭示了AIBP介导的胆固醇代谢和Notch信号之间的新机制联系，暗示AIBP可能是病理条件下调节血管生成的药物靶点。
Angiogenesis improves perfusion to the ischemic tissue following acute vascular obstruction. Angiogenesis in pathophysiological settings reactivates signaling pathways involved in developmental angiogenesis. We showed previously that apoA-I binding protein (AIBP)-regulated cholesterol efflux in endothelial cells (ECs) controls zebrafish embryonic angiogenesis. This study is to determine whether loss of AIBP affects angiogenesis in mice during development and under pathological conditions, and to explore the underlying molecular mechanism. In this paper, we report the generation of AIBP knockout (Apoa1bp−/−) mice, which are characterized of accelerated postnatal retinal angiogenesis. Mechanistically, AIBP triggered relocalization of γ-secretase from lipid rafts to non-lipid rafts where it cleaved Notch. Consistently, AIBP treatment enhanced DLL4-stimulated Notch activation in human retinal ECs. Increasing HDL levels in Apoa1bp−/− mice by crossing them with apoA-I transgenic mice rescued Notch activation and corrected dysregulated retinal angiogenesis. Notably, the retinal vessels in Apoa1bp−/− mice manifested normal pericyte coverage and vascular integrity. Similarly, in the subcutaneous Matrigel plug assay, which mimics ischemic/inflammatory neovascularization, angiogenesis was dramatically upregulated in Apoa1bp−/− mice and associated with a profound inhibition of Notch activation and reduced expression of downstream targets. Furthermore, loss of AIBP increased vascular density and facilitated the recovery of blood vessel perfusion function in a murine hindlimb ischemia model. In addition, AIBP expression was significantly increased in human patients with ischemic cardiomyopathy. Our data reveal a novel mechanistic connection between AIBP-mediated cholesterol metabolism and Notch signaling, implicating AIBP as a possible druggable target to modulate angiogenesis under pathological conditions.